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Ophthalmic Genetics and Visual Function Branch

Our research

OGVFB Staff Screen Shot

As a center of excellence for clinical investigation, basic research and treatment of heritable ocular disorders, the Branch aims to: 1) understand the genetic, molecular, cellular and developmental mechanisms of inherited eye disease; 2) to understand the pathophysiology and natural history of inherited eye disease through deep clinical phenotyping, including the use of advanced imaging, psychophysical and electrophysiology techniques; and 3) translate these findings into proof-of-concept clinical trials in order to identify treatments for inherited eye diseases. The Ophthalmic Genetics Branch has a team of skilled and devoted clinician-scientists, molecular geneticists, genetic counselors, engineers, and technologists, who have at their disposal a strong array of clinical and molecular genetic diagnostic tools for the investigation of families and patients with inherited retinal disorders. Over many years of clinical research, the Branch has compiled an impressive database of patients with fully characterized phenotypic information on a host of heritable ocular disorders. These disorders are amenable to further molecular genetic analysis and to future treatment protocols.

Some of the Branch's research interests include:

ABCA4 Retinopathy: ABCA4 is a photoreceptor protein important in the recycling of retinoids during the visual cycle. Mutations in the ABCA4 gene lead to a spectrum of phenotypes. The most common presentation is Stargardt disease, where central vision loss develops in the first few decades of life, often accompanied by retinal flecks composed of lipofuscin and macular atrophy. More severely affected patients may develop a more widespread cone-rod or rod-cone degeneration.

Recently, several approaches to slowing or stopping the progression of ABCA4 retinopathy have been proposed, including gene therapy, stem cell based therapy and small molecule therapy. Therapeutic trials are on the horizon. However, because most patients with ABCA4 retinopathy progress at a slow rate, determining whether a treatment strategy is effective will depend upon developing robust clinical outcome measures that can be observed over a relatively short period of time.

To this end, we have established a natural history protocol for patients with ABCA4 retinopathy. The goals of this clinical research protocol are to determine which clinical tests are likely to be the most useful outcome variables in a future clinical trial and to better understand the genetic factors that regulate the severity of disease/rate of progression.


Albinism: Albinism is an inherited disorder characterized by reduced melanin pigment in the hair, skin and eyes. For reasons that are not completely clear, patients with albinism also have several developmental eye abnormalities that limit their best-corrected visual acuity, including foveal hypoplasia and an abnormal projection pattern of their optic nerve pathways. This observation raises an important clinical question-if we had a way of improving pigmentation at early stages of postnatal development, when the fovea is still maturing, could we improve vision in patients with albinism.

We have recently shown that nitisinone, an FDA-approved drug used in the treatment of hereditary tyrosinemia, type1 (HT1), is able to improve ocular and fur pigmentation in a mouse model of one form of albinism, OCA1B. We are currently researching whether this and other compounds may be effective in other mouse models of albinism. We are also conducting a pilot clinical trial to determine whether nitisinone is effective in improving melanin pigment in adult patients with OCA1B. If it is effective, we intend to extend this trial to include more patients, including those of younger ages. Another goal of this trial is to determine which clinical outcome measures are most useful in treating patients with albinism.

In parallel, we are attempting to develop other treatment strategies for albinism that may work via different mechanisms, mostly focused on tyrosinase-the first and rate-limiting step in melanin production. These studies remain at the pre-clinical stage and include ways of improving intrinsic tyrosinase activity, improving the intracellular trafficking/folding of tyrosinase, and increasing the expression level of tyrosinase.

Coloboma: Uveal coloboma is a potentially-blinding congenital ocular malformation caused by the failure of the optic fissure to close during the 5th week of human gestation. Uveal coloboma is most often sporadic, although autosomal dominant, autosomal recessive and X-linked pedigrees have been described. Our current understanding of the genetics of uveal coloboma is limiting, making genetic counseling and molecular diagnosis difficult.

A major goal of our research is to understand the developmental mechanisms and the genetics of uveal coloboma in order to better serve patients and their families. We also seek to understand other systemic medical issues patients with coloboma experience.

Dark Adaptation in Age-Related Macular Degeneration

eyeGENE®: The National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE®) is a genomic medicine initiative created by the National Eye Institute (NEI), part of the National Institutes of Health (NIH), in partnership with clinics and laboratories across the vision research community. The core mission of eyeGENE® is to facilitate research into the causes and mechanisms of rare inherited eye diseases and accelerate pathways to treatments. eyeGENE® was designed to achieve this goal through clinical and molecular diagnosis coupled with granting controlled access to clinical and genetic information in a data repository, to DNA in a biorepository, and to individuals consented to participate in research and clinical trials.

The eyeGENE® Network currently includes a Coordinating Center at the NEI, CLIA†-approved molecular genetic testing laboratories around the Nation, a patient registry, controlled-access centralized biorepository for DNA, and a curated de-identified genotype / phenotype database.

These components stimulate patient and eye health care provider interest in genetics-based clinical care and generate involvement in ophthalmic research, thereby accelerating vision research and treatment development for these diseases.

† – Clinical Laboratory Improvements Amendments

Genetic Determinants of Plaquenil Toxicity:

Induced Pluripotent Stem Cells (iPSCs) to Study and Treat Retinal Pigment Epithelium Disorders: Dysfunctions in the retinal pigment epithelium (RPE) of the eye are thought to be the initiating events leading to degenerative eye diseases. Therefore, a better understanding of the disease initiating pathways in RPE will provide a basis for therapeutic interventions. In vitro disease models are being developed to study patient-specific disease processes, to set up high through drug screens, and to develop cell-based therapy for retinal degenerative diseases. Skin biopsies from patients with clinically diagnosed degenerative eye diseases are being used to derive iPS cells. RPE cells differentiated from such iPS cells are used to study events that have led to disease initiation and progression. In collaboration with the NIH Center for Advancing Translational Sciences, we are developing high throughput screens to identify small molecules that can provide potential therapeutic interventions for such degenerative eye diseases. In collaboration with the new NIH Center for Regenerative Medicine, we are developing clinical-grade iPSC-derived RPE tissue for cell-based therapy, in compliance with current Good Manufacturing Practices.

Inherited retinal degenerations and allied diseases

Molecular Genetics of Inherited Eye Disease: This section has been involved in a number of different to study inherited visual diseases affecting the lens and retina as well as diseases affecting multiple ophthalmic structures such as glaucoma and myopia.

One approach to understanding inherited visual diseases uses principles of positional cloning to identify genes important in human inherited diseases. Such diseases currently undergoing linkage analysis, gene isolation, or characterization of mutations include Usher syndrome, retinal degenerations, inherited cataracts, Bietti crystalline dystrophy, corneal dystrophies, glaucoma, and high myopia.

A second approach is to attempt to establish associations between sequence changes in candidate genes and specific phenotypes. This type of study is most applicable to prevalent multifactorial diseases with a complex inheritance pattern, and is currently being used for age related cataracts, myopia, and glaucoma.

Once a candidate gene has been identified and confirmed, the biochemical and pathophysiological implications of identified mutations are explored both in vitro through recombinant expression of native and mutant proteins and in vivo through transgenic expression of pathological proteins in a variety of model systems including transgenic and knockout mice and zebrafish, These approaches provide both increased understanding of vision biology and the basis for rational design of diagnostic and therapeutic approaches.

Usher Syndrome

X-linked Juvenile Retinoschisis (XLRS): XLRS causes vision loss primarily in young males due to splitting (schisis) of retinal layers.  The OGVFB is conducting a natural history study of XLRS to determine the best outcome variables for following the disease during a clinical treatment trial. We have begun a pilot clinical trial of gene therapy for XLRS.  Given that gene replacement therapies are at the cutting edge of medical research, we are also studying the expectations of patients considering and enrolling in this study.

Ophthalmic Genetics and Visual Function Branch key staff

Key staff table
Name Title Email Phone
Tiziana Cogliati, Ph.D. Deputy Branch Chief 301-451-5954
Cathy Geer Administrative Laboratory Manager 301-496-5360
Jairo Mejia Administrative Laboratory Manager 301-451-9939
Amy Thompson, Ph.D. Science Writer

Last updated: October 15, 2021